Background-Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function. Methods and Results-mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c ϩ/Ϫ hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c ϩ/Ϫ than in wild-type. Perfusion with the ␤-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c ϩ/Ϫ hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c ϩ/Ϫ with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c.Conclusions-These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF. (Circ Cardiovasc Genet. 2011;4:123-133.)Key Words: action potentials Ⅲ atrium Ⅲ fibrillation Ⅲ genes Ⅲ transgenic mice Ⅲ genetic predisposition A trial fibrillation (AF) is by far the most common sustained arrhythmia and causes important morbidity and mortality. 1,2 Unfortunately, the causes of the arrhythmia are not sufficiently understood to allow effective therapy to prevent AF. 3,4 Both rare and common forms of AF can be heritable, and the genes responsible may provide important clues toward therapy. Familial forms of AF associate with mutations in genes encoding sodium and potassium ion channels, connexin40, the natriuretic peptide precursor A (NPPA) but also transcription factor genes, either in candidate or genome-wide association studies. 3,[5][6][7][8] Editorial see p 105 Clinical Perspective on p 133A polymorphic locus on chromosome 4q25 (SNP rs2200733) associates with AF, particularly of early onset, in several independent studies of European and Asian populations 9,10 and conveys an approximately 1.7-fold risk of developing AF. 11 This locus is intergenic, with the gene in closest proximity being PITX2, which encodes a homeobox transcription factor of the paired type. Mutations of PITX2 are responsible for autosomal dominant anterior eye defects, including the Axenfeld-Rieger syndrome, 12 albeit without reports of AF in affected patients.During embryonic development in ...

Over the last decade, mouse models have become a popular instrument for studying cardiac arrhythmias. This review assesses in which respects a mouse heart is a miniature human heart, a suitable model for studying mechanisms of cardiac arrhythmias in humans and in which respects human and murine hearts differ. Section I considers the issue of scaling of mammalian cardiac (electro) physiology to body mass. Then, we summarize differences between mice and humans in cardiac activation (section II) and the currents underlying the action potential in the murine working myocardium (section III). Changes in cardiac electrophysiology in mouse models of heart disease are briefly outlined in section IV, while section V discusses technical considerations pertaining to recording cardiac electrical activity in mice. Finally, section VI offers general considerations on the influence of cardiac size on the mechanisms of tachy-arrhythmias.

Background: Smartwatches that are able to record a bipolar ECG and Einthoven leads were recently described. Nevertheless, for detection of ischemia or other cardiac diseases more leads are required, especially Wilson’s chest leads. Objectives: Feasibility study of six single-lead smartwatch (Apple Watch Series 4) ECG recordings including Einthoven (I, II, III) and Wilson-like pseudo-unipolar chest leads (Wr, Wm, Wl). Methods: In 50 healthy subjects (16 males; age: 36 ± 11 years, mean ± SD) without known cardiac disorders, a standard 12-lead ECG and a six single-lead ECG using an Apple Watch Series 4 were performed under resting conditions. Recording of Einthoven I was performed with the watch on the left wrist and the right index finger on the crown, Einthoven II was recorded with the watch on the left lower abdomen and the right index finger on the crown, Einthoven III was recorded with the watch on the left lower abdomen and the left index finger on the crown. Wilson-like chest leads were recorded corresponding to the locations of V1 (Wr), V4 (Wm) and V6 (Wl) in the standard 12-lead ECG. Wr was recorded in the fourth intercostal space right parasternal, Wm was recorded in the fifth intercostal space on the midclavicular line, and Wl was recorded in the fifth intercostal space in left midaxillary line. For all Wilson-like chest lead recordings, the smartwatch was placed on the described three locations on the chest, the right index finger was placed on the crown and the left hand encompassed the right wrist. Both hands and forearms also had contact to the chest. Three experienced cardiologists were independently asked to allocate three bipolar limb smartwatch ECGs to Einthoven I–III leads, and three smartwatch Wilson-like chest ECGs (Wr, Wm, Wl) to V1, V4 and V6 in the standard 12-lead ECG for each subject. Results: All 300 smartwatch ECGs showed a signal quality useable for diagnostics with 281 ECGs of good signal quality (143 limb lead ECGs (95%), 138 chest lead ECGs (92%). Nineteen ECGs had a moderate signal quality (7 limb lead ECGs (5%), 12 chest lead ECGs (8%)). One-hundred percent of all Einthoven and 92% of all Wilson-like smartwatch ECGs were allocated correctly to corresponding leads from 12-lead ECG. Forty-six subjects (92%) were assigned correctly by all cardiologists. Allocation errors were due to similar morphologies and amplitudes in at least two of the three recorded Wilson-like leads. Despite recording with a bipolar smartwatch device, morphology of all six leads was identical to standard 12-lead ECG. In two patients with acute anterior myocardial infarction, all three cardiologists recognized the ST-elevations in Wilson-like leads and assumed an occluded left anterior descending coronary artery correctly. Conclusion: Consecutive recording of six single-lead ECGs including Einthoven and Wilson-like leads by a smartwatch is feasible with good ECG signal quality. Thus, this simulated six-lead smartwatch ECG may be useable for the detection of cardiac diseases necessitating more than one ECG lead li...